Published Ahead of Print on February 17, 2016 as 10.1212/WNL.

0000000000002478
CLINICAL
IMPLICATIONS OF
NEUROSCIENCE
Dorsal horn circuitry
RESEARCH
Complexity and implications for mechanisms of neuropathic pain
Section Editor
Eduardo E.
Benarroch, MD

Eduardo E. Benarroch, The transmission of pain involves several types of pri-
MD mary unmyelinated Ad- and unmyelinated C afferents
from neurons in in the dorsal root (or trigeminal) gan-
glion; these afferents activate second-order spinothala-
Correspondence to mic and spinobulbar projection neurons in the dorsal
Dr. Benarroch:
benarroch.eduardo@mayo.edu horn (or trigeminal nucleus caudalis). The dorsal horn is
not a simple relay station but rather a site of complex
processing and gating of nociceptive information via
circuits involving different subtypes of excitatory or
inhibitory interneurons. These neurons are the target
of descending pain-modulatory influences from the ros-
tral ventromedial medulla and other regions. Pain cir-
cuits also participate in the relay and processing of
the sensation of itch. Specific molecular markers, such
as transient receptor potential (TRP) channels and Mas-
related G-protein–coupled receptor (Mrgpr) subtypes,
have allowed the identification of different subtypes of
primary afferents transmitting pain and itch sensations.
The application of transgenic and ablation techniques
has provided insight into the heterogeneity of excitatory
or inhibitory interneurons and their involvement in dor-
sal horn circuits regulating transmission and gating of
pain and itch. Excitatory interneurons have a major role
in both normal and abnormal transmission of sensory
input to the projection neurons; inhibitory interneurons
are critically involved in gating these inputs. These find-
ings provide new insights into the pathophysiology of
the manifestations of neuropathic pain, including spon-
taneous pain, hyperalgesia, and mechanical allodynia, as
well as neuropathic itch. There are several reviews on all
these topics.1–19 This review is focused on the spinal
dorsal horn, although similar processes likely underlie
facial trigeminal-mediated pain.
BASIC COMPONENTS OF THE DORSAL HORN
CIRCUITRY The dorsal horn of the spinal cord is classi-
cally subdivided into 5 cytoarchitectonic laminae accord-
ing to Rexed20 (figure 1). Laminae I and II constitute the
superficial dorsal horn. Lamina I primarily contains
different subtypes of projection (spinothalamic and spi-
nobulbar) neurons. Lamina II or substantia gelatinosa is
subdivided into an outer and an inner region, both
containing different subtypes of local excitatory or inhib-
itory interneurons. Laminae III to V constitute the deep
dorsal horn and contain different subtypes of projection
neurons as well as interneurons. Both the projection
neurons and local interneurons receive lamina-specific
input from different subtypes of primary afferents from
dorsal root ganglion neurons.
Primary afferents. There are several populations of primary
afferents that differ in their axon diameter, response to
stimuli, neurochemical characteristics, and targets in the
dorsal horn. The primary neurotransmitter of all these af-
ferents is L-glutamate. This review focuses on primary
afferents innervating the skin (table 1).
Nociceptors. There are several subtypes of small
myelinated Ad fibers and unmyelinated C nociceptors
innervating the skin.1,2 They can be subdivided into 2
main neurochemical populations. Peptidergic afferents
contain neuropeptides such as substance P and calcitonin
gene-related peptide; they transmit painful heat stimuli
and terminate at both projection neurons and interneu-
rons in the most superficial laminae of the dorsal horn
(lamina I and outer lamina II). These afferents express the
transient receptor potential vanilloid 1 (TRPV1) recep-
tor, which renders them sensitive to heat and capsaicin,
and the transient receptor potential ankyrin 1 (TRPA1)
receptor, which responds to several chemical irritants. In
contrast, nonpeptidergic C afferents transmit mechanical,
but not heat-induced pain, and target interneurons in
inner lamina II. These nonpeptidergic populations
express lectin IB4 and the Mrgpr member D
(MrgprD).1,2 Like all primary nociceptive afferents,
they use L-glutamate as their primary transmitter.
Pruriceptors. Some cutaneous C-nociceptive neurons
also respond to chemicals that elicit the sensation of itch,
such as histamine; these afferents are referred to as pru-
ritoceptors or pruriceptors.9,10 They detect a wide variety
of pruritogenic stimuli via multiple types of G-protein–
coupled receptors, including H1 and H4 receptors for
histamine, the Mas-related G-protein–coupled receptors

GLOSSARY
BDNF 5 brain-derived neurotrophic factor; GABA 5 g-aminobutyric acid; Mrgpr 5 Mas-related G-protein–coupled receptor;
NK1R 5 neurokinin-1 receptor; TRP 5 transient receptor potential; TRPA1 5 transient receptor potential ankyrin 1;
TRPM8 5 transient receptor potential, melastatin 8 type; TRPV1 5 transient receptor potential, vanilloid type 1.

From the Department of Neurology, Mayo Clinic, Rochester, MN.

Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

© 2016 American Academy of Neurology 1

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Figure 1 Transmission of afferent inputs from nociceptors and tactile receptors to the dorsal horn

Peptidergic and nonpeptidergic Ad- and C-nociceptor afferents, low-threshold Ab mechanoreceptive afferents, and low-
threshold C-mechanoreceptive afferents (not shown) provide input to projection neurons and interneurons in different
laminae of the dorsal horn. Nociceptive projection neurons express the neurokinin 1 receptor (NK1R) and are primarily
located in lamina I; other projection neurons are wide dynamic range neurons and are distributed in laminae III, IV, and V, as
well as laminae III and IV. Lamina II is subdivided into an outer (IIo) and an inner region (IIi) containing different subtypes of
local excitatory or inhibitory interneurons. Peptidergic afferents transmit painful heat stimuli and terminate in both lamina I
projection neurons and lamina IIo interneurons. Nonpeptidergic afferents transmit mechanical-induced pain to excitatory
interneurons in lamina IIi, which convey these inputs to lamina I projection neurons via a polysynaptic excitatory pathway
that includes central (Ce) and vertical (V) neurons. Low threshold Ab mechanoreceptors primarily target laminae III-V.
Inhibitory g-aminobutyric acid (GABA)/glycinergic interneurons, primarily islet cells (I), receive inputs from both low-thresh-
old mechanoreceptors and nociceptors and gate transmission of nociceptive input in the dorsal horn and prevent the access
of low-threshold mechanoreceptive input to excitatory interneurons; inhibitory interneurons also control the excitability of
lamina III-V projection neurons, which receive both nociceptive and non-nociceptive input.

MrgprA3 and MrgprD, and the proteinase associated
receptor 2, among others.9,10,21 Itch-sensing G-protein–
coupled receptors trigger downstream signaling cascades
that gate TRP channels such as TRPV1 and TRPA1.22,23
For example, histamine elicits itch in humans via
mechano-insensitive C afferents.24 Many of these affer-
ents are also nociceptive and express both H1 and
TRPV1 receptors; the presence of TRPV1 receptors is
required for histamine to elicit itch.22,25 However, activa-
tion of afferents expressing both TRPV1 and MrgprA3
receptors and responding to the antimalarial agent chlo-
roquine elicits itch but not pain.26 Other subtypes of
afferents also respond to specific groups of pruritogens.
For example, itch produced by the dietary supplement
b-alanine involves MrgprD-expressing afferents.21
Low-threshold C mechanoreceptors. There are 2 subgroups
of unmyelinated C afferents that respond to low-
intensity (nonpainful) stimuli and have been associated
with the affective sensation of pleasant touch.27 The larg-
est population expresses tyrosine hydroxylase and the
vesicular glutamate transporter subtype 3; a second pop-
ulation expresses the MrgprB4 receptor and terminates
in outer lamina II.
Low-threshold Ab mechanoreceptors. Large-diameter, mye-
linated Ab afferents transmit nonpainful inputs from low
mechanical threshold tactile mechanoreceptors involved

2 Neurology 86 March 15, 2016

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Table 1 Primary skin afferents in the dorsal horn
Fiber type (diameter)
Ab type (large myelinated,
10 mm)
Ad type (small myelinated,
2.5 mm)
C type (unmyelinated, 1 mm)
Abbreviations: CGRP 5 calcitonin gene-related peptide; Mrgpr 5 Mas-related G-protein–coupled receptor; TRPM8 5 transient receptor potential, melastatin 8
type; TRPA1 5 transient receptor potential ankyrin 1; TRPV1 5 transient receptor potential, vanilloid type 1.
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Conduction
velocity Receptor type Modality
21
60 m$s Low-threshold mechanoreceptor Discriminative touch
12 m$s21 Peptidergic nociceptor Heat-triggered pain
Nonpeptidergic nociceptor Mechanical-triggered
pain
Cold receptor Innocuous cold
,2 m$s21 Peptidergic nociceptor Heat-triggered pain
Nonpeptidergic nociceptor Mechanical-triggered
pain
Warm receptor Innocuous warmth
Pruriceptors Itch
Low-threshold mechanoreceptor, Emotional touch
mechanoreceptor
in discriminative touch. These afferents express d-type
opioid receptors.28 Low-threshold Ab mechanosensitive
afferents arborize in an area that extends from inner lam-
ina II to laminae V and target different neuronal subpo-
pulations in specific laminae.1,2,4
Thermoreceptors. Cutaneous primary sensory neu-
rons involved in thermosensation include both C
and Ad fibers; C fibers innervate I and II and Ad
fibers layers I and V. Thermal sensation involves
selective temperature-dependent activation of differ-
ent subtypes of TRP and other cation channels in
these afferents. For example, C afferents responsive
to cold express the transient receptor potential
melastatin 8 (TRPM8) receptor and terminate in
lamina I.29 The mechanisms underlying thermal sen-
sation have been reviewed30 and are not discussed here.
Projection neurons. The projection (or output) neurons
of the dorsal horn transmit sensory information via
the spinothalamic tract and several parallel pathways.
These neurons are located in lamina I and in laminae
III-V and receive inputs from primary afferents both
directly and via excitatory interneurons (figure 1).
Despite their importance, projection neurons only
constitute a small proportion of the total neuronal
population in the dorsal horn.
Lamina I. Lamina I contains the majority of spino-
thalamic tract projection neurons. They include
nociceptive-specific neurons responsive to heat or me-
chanically induced pain, neurons responsive to innocu-
ous cooling, and neurons responsive to noxious heat,
noxious mechanical (pinch), or cold stimuli.31 Some
lamina I neurons may also be activated by pruritic agents
such as histamine. The majority of nociceptive lamina I
Neurochemical marker
D-opioid receptor
Substance P, CGRP, TRPV1 and TRPA1 channels,
m opioid receptor
MrgprD, D-opioid receptor
TRMP8 channel
Substance P, CGRP, TRPV1 and TRPA1 channels,
m opioid receptor
MrgprD, d-opioid receptor
Substance P TRPV1
Substance P, CGRP, natriuretic polypeptide B,
TRPV1 H1, MrgprA3
Mrgpr4, tyrosine hydroxylase
neurons have a multipolar or fusiform morphology and
express the neurokinin-1 receptor (NK1R) for substance
P.32 These neurons convey discriminative aspects of
pain, such as its location and quality, but also participate
in emotional aspects of pain sensation via parallel spino-
thalamic pathways.1 The main targets of these neurons
are the ventral posterior complex of the thalamus (ven-
tral posterior lateral, ventral posterior medial, and ventral
posterior inferior nuclei), which project to the primary
and secondary somatosensory cortex,33 and the posterior
part of the ventral medial nucleus of the thalamus,
which projects to the dorsal posterior insular cortex.34
Other projection targets of NK1R lamina I neurons
include the lateral parabrachial nucleus, which provides
access of nociceptive information to the amygdala and
hypothalamus; and the periaqueductal gray, which par-
ticipates in central pain modulatory circuits.
Whereas up to 80% of lamina I dorsal horn neu-
rons express NK1R and transmit heat-triggered pain
input from peptidergic C afferents, genetic deletion
or pharmacologic blockade of either substance P or
the NK1 receptor has limited effect on pain transmis-
sion in either experimental animals35 or humans.36
This emphasizes the importance of other afferent in-
puts, including glutamatergic inputs via excitatory
interneurons in lamina II in driving the activity of
nociceptive lamina I projection neurons (see below).
Lamina I also contains pyramidal neurons that lack
NK1R; these neurons may receive non-nociceptive in-
puts from low-threshold C mechanoreceptors signaling
affective touch, or from TRMP8-expressing C afferents
responding to innocuous cooling.29 Peripheral inflam-
mation may elicit de novo expression of NK1R in these
Neurology 86 March 15, 2016 3
 pyramidal neurons, thereby enabling these neurons to
respond to noxious stimuli.37
Deep dorsal horn. The projection neurons located in
the deep dorsal horn (laminae III–V) are wide dynamic
range neurons that respond to both innocuous and nox-
ious stimuli; these neurons have wide receptive fields and
code stimulus intensity. The innocuous inputs to these
neurons derive from large-diameter Ab afferents. Lamina
III wide dynamic range neurons express NK1R receptors
and have long dorsally directed dendrites that penetrate
the superficial dorsal horn (lamina I–II) and may thus be
activated by peptidergic afferents. Lamina V neurons also
extend dendrites to superficial lamina II and may also be
directly activated by primary afferents, but they also
receive inputs from excitatory interneurons of deep lam-
ina II targeted by nonpeptidergic nociceptive afferents38
(figure 1). Lamina V neurons contribute to the spino-
thalamic tract and also target subcortical structures
involved in affective processing of pain sensation, such
as the amygdala and hypothalamus, and, at least in mice,
also the globus pallidus.38
Interneurons. Dorsal horn interneurons have a critical
role in transmission and gating of nociceptive trans-
mission. They occupy laminae I to III, although the
majority are concentrated in lamina II.1,2 The dorsal
horn interneurons constitute a heterogeneous popula-
tion and include several subtypes that differ in their
morphology, neurochemistry, electrophysiology, and
connectivity1,6,39–47 (table 2). The main morphologic
types are islet, central, radial, and vertical (also referred to
as stalked) cells, which can be either excitatory or inhib-
itory. Inhibitory interneurons utilize g-aminobutyric acid
(GABA), glycine, or both as their neurotransmitter. In
general, the majority of these inhibitory interneurons are
islet cells; others have central and vertical morphologies.
Excitatory interneurons utilize L-glutamate and include
radial and most of the vertical and central cells.1,39–47
Inhibitory interneurons. Inhibitory interneurons con-
stitute approximately one-third of the neuronal
population in the dorsal horn. There are several
Table 2 Main population of dorsal horn interneurons
Type Inhibitory
Morphology (most common) Islet cell
Primary neurotransmitter GABA, glycine, or both; dynorphin in
some cases
Neurochemical markers and Parvalbumin, neuropeptide Y, galanin,
subtypes (examples) neuronal NOS
Afferent input Relatively weak
Typical ion channel (current) Hyperpolarization-activated cyclic
nucleotide gated channel 1 and 4
Typical discharge pattern Tonic spiking
Abbreviation: GABA 5 g-aminobutyric acid.
4 Neurology 86 March 15, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
nonoverlapping subpopulations of GABA/glycinergic
interneurons that may coexpress parvalbumin, dynor-
phin, neuropeptide Y, galanin, or neuronal nitric oxide
synthase; these subpopulations also differ in their electro-
physiologic properties and afferent input.40–42 For exam-
ple, tonic-spiking parvalbumin-expressing inhibitory
interneurons primarily receive input from low-threshold
Ab primary afferents and establish axo-axonic synapses
with myelinated afferents innervating excitatory inter-
neurons.45 In contrast, inhibitory neurons expressing
galanin, neuropeptide Y, neuronal nitric oxide syn-
thase, or dynorphin receive inputs from nociceptive
afferents and synapse on either excitatory or other
inhibitory interneurons.1,39–41,45
Excitatory interneurons. Excitatory interneurons include
a larger and even more heterogeneous population than
inhibitory neurons.1,39,40,42–46 Whereas all excitatory neu-
rons are glutamatergic, they can be subdivided into dif-
ferent subpopulations according to the expression of
vesicular glutamate transporters; somatostatin; somato-
statin 2A, opioid or glutamate receptors; and markers
such as protein kinase Cg or gastrin-releasing peptide.
Many excitatory neurons express the calcium-binding
protein calretinin.44 Selective subpopulations of excitatory
interneurons may receive inputs from distinct primary
afferents. For example, vertical interneurons expressing
somatostatin receive inputs from both low-threshold
Ab and high-threshold nociceptive Ad/C mechanorecep-
tors42; neurons expressing the vesicular glutamate trans-
porter 3 or protein kinase Cg primarily relay inputs from
low-threshold Ab mechanoreceptors47; and gastrin-
releasing peptide neurons are activated by pruriceptors.25
Excitatory interneurons also vary in their firing pattern,
which is largely determined by the presence of A-type
currents via Kv4 channels1,6 (table 2).
PARALLEL LINES FOR TRANSMISSION OF
AFFERENT INFORMATION IN THE DORSAL
HORN Peptidergic vs nonpeptidergic nociceptive afferents.
Selective ablation studies show that subsets of nociceptors
are selective for a particular modality and provide for
Excitatory
Vertical (stalked), central, and radial cells
L-glutamate
Somatostatin; somatostatin A2 receptor, protein
kinase C-g, gastrin-releasing peptide, gastrin-
releasing peptide receptor
Strong
Kv4.2, Kv4.3 (A-current)
Transient (central cells), delayed (vertical cells)
 labeled lines for nociceptive transmission.38,48,49 Peptider-
gic TRPV1 receptor–expressing nociceptors signal heat-
induced pain and target the most superficial laminae of
the dorsal horn, including both NK1R-expressing
projection neurons of lamina I and interneurons in
outer lamina II. These peptidergic afferents engage
different subsets of inhibitory50 and excitatory51
neurons of the superficial dorsal horn. In contrast,
nonpeptidergic MrgprD-expressing afferents signal
mechanically induced pain and target excitatory
interneurons of inner lamina II, which then convey
noxious mechanical inputs to lamina I via polysynaptic
pathways (see below). Whereas nonpeptidergic C
afferents activate all types of excitatory interneurons,
they may not directly target inhibitory interneurons.52
Consistent with these differences, peptidergic afferents
express m-opioid receptors, whereas nonpeptidergic
afferents express d-opioid receptors.53
Itch afferents. There is evidence indicating that there is
a labeled line for itch sensation.7–10,21,25 Studies in
mice elucidated an itch-specific circuitry in the
superficial dorsal horn. 25 This circuit involves C
pruriceptor afferents that release natriuretic polypeptide
B (also referred to as brain natriuretic peptide) in
addition to L-glutamate; this peptide activates a
group of interneurons expressing gastric-releasing
peptide, which in turn acts via its receptors on a third
population of excitatory neurons that convey the itch
sensation via lamina I spinothalamic neurons.25
ROLE OF INTERNEURONS IN DORSAL HORN
CIRCUITS Feed-forward excitatory circuits for nociceptive
and pruritogenic inputs. Nociceptive afferents engage
spinothalamic neurons both directly and via a parallel
feed-forward circuit through excitatory interneurons
(figure 1). Whereas the NK1R-expressing nociceptive
lamina I neurons receive direct input from peptidergic
afferents encoding heat-pain, they receive indirect input
from nonpeptidergic afferents encoding mechanical pain
via a polysynaptic ventral-to-dorsal pathway that involves
the sequential activation of excitatory interneurons
from inner (ventral) to outer (dorsal) lamina II.1,42,54
Nonpeptidergic mechanosensitive C nociceptors
target central interneurons in inner lamina II, which
in turn excite the vertical cells in outer lamina II;
vertical neurons send excitatory projections to NK1R-
expressing spinothalamic neurons in lamina I.54 This
interneuronal pathway provides for the polymodal
responses of lamina I spinothalamic neurons to both
noxious heat and noxious mechanical stimuli. Since
vertical excitatory interneurons in outer lamina II also
receive direct input from Ad nociceptors, this circuit
provides a backup excitatory drive for nociceptive
transmission in lamina I. There is also a parallel
dorsal-to-ventral drive to projection neurons in the
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
deep dorsal horn; lamina II excitatory neurons may
relay nonpeptidergic C-afferent inputs to lamina V.38
Transmission of itch sensation also involves a serial
excitatory pathway activated by C afferents releasing
natriuretic peptide B and including interneurons
releasing gastrin-released peptide and their targets.25
Selective deletion of the gene encoding the testic-
ular orphan receptor 4 in mice, which depletes subsets
of excitatory interneurons, emphasizes the impor-
tance of these neurons for the full expression of pain
and itch sensations.55
Access of low-threshold mechanoreceptive input to
nociceptive neurons. Transmission of innocuous mechan-
ical (touch) input to the superficial dorsal horn also in-
volves a sequential pathway of dorsally projecting
excitatory interneurons in lamina II.42,47,54,56 Low-
threshold Ab mechanoreceptors activate excitatory
interneurons in lamina III that express the vesicular
glutamate transporter-3; these neurons project to
protein kinase Cg-expressing interneurons in inner
lamina II, which in turn sequentially activate central
cells in inner lamina II, vertical cells in outer lamina II,
and finally NK-1-expressing nociceptive projection
neurons in lamina I.47 The convergence of direct Ad/C
mechanical nociceptor input and excitatory interneuron-
mediated low-threshold Ab mechanoreceptor input on
vertical excitatory interneurons in outer lamina II
provides a substrate for innocuous mechanical stimuli
to elicit pain (mechanical allodynia), as discussed
below. Like Ab afferents, C-tactile afferents (low-
threshold C mechanoreceptors) also project to inner
lamina II and have access, via excitatory interneurons,
to wide dynamic range projection neurons located
in lamina I and lamina V,57 thereby potentially
contributing to mechanical allodynia. However,
in normal conditions, the access of inputs from
low-threshold mechanoreceptors to nociceptive neurons
is prevented by surrounding feed-forward inhibition.42
Feed-forward inhibitory circuits. As all primary affer-
ents are excitatory, local inhibitory interneurons acti-
vated by these afferents serve as a gate control mechanism
to reduce transmission of nociceptive, itch, and tactile
information to spinothalamic neurons. According to
the gate control theory of Melzack and Wall,58 large-
fiber afferents conveying innocuous stimuli activate
inhibitory neurons in the substantia gelatinosa,
which in turn inhibit dorsal horn projection neurons
that transmit inputs from nociceptive afferents.
Parvalbumin-expressing inhibitory GABA/glycinergic
islet cells distributed in inner lamina II through
lamina IV may provide the substrate for this
inhibitory gate control mechanism, as they receive
input from low-threshold primary afferents (figure 1).
Some islet cells may also receive inputs from
low-threshold mechanosensitive C fibers and may
Neurology 86 March 15, 2016 5
 therefore contribute to the pain inhibitory effects of
innocuous stimuli.59 Inhibition in the dorsal horn
may occur via both presynaptic and postsynaptic
mechanisms. For example, parvalbumin-expressing
GABAergic neurons in inner lamina II and lamina
III provide axo-axonic inhibition of primary
myelinated afferents, thereby gating the access
of low-threshold afferent input to excitatory
interneurons.45 Deletion studies indicate that
specific groups of inhibitory GABAergic60,61 or
glycinergic62 interneurons are also involved in
tonic inhibition of the itch pathway. Inhibitory
islet cells may mediate some of the descending
monoaminergic modulatory control on pain
transmission.40,63 The gate control theory also
proposes that noxious stimuli would open the gate
by inhibiting the inhibitory interneurons.58 Consistent
with this hypothesis, some inhibitory islet or central
cells receive direct input from nociceptive substance
P–containing C fibers and are activated by noxious
stimuli; these cells could promote pain transmission
by inhibiting other inhibitory islet cells.50
CLINICAL CORRELATIONS: DORSAL HORN,
CENTRAL SENSITIZATION, AND NEUROPATHIC
PAIN Neuropathic pain reflects injury of the sensory
system, leading to reduced threshold for pain sensa-
tion resulting in spontaneous pain, increased ampli-
tude and duration of pain responses (hyperalgesia),
and triggering of pain by innocuous stimuli (allo-
dynia). These diverse manifestations reflect various
combinations of disturbances of nociceptive transmis-
sion and processing at the level of peripheral nocicep-
tors, dorsal horn (or trigeminal nucleus caudalis), and
supraspinal targets. Itch is an unpleasant sensory and
emotional sensation that produces the desire to scratch
and has several common features with pain.7 For exam-
ple, itch-producing agents, such as histamine or
capsaicin, activate nociceptive primary afferents and
can generate simultaneously itch and pain sensations64;
persons with congenital insensitivity to pain are also
typically insensitive to itch.65,66 However, itch and
pain are independent sensations that may be inversely
related to one another; for example, nociceptive
counterstimuli (scratching) transiently relieves itch,
whereas analgesic m-opioid receptor agonists produce
itch.7 Chronic neuropathic pain, with or without
associated itch, is the consequence of peripheral and
central sensitization within the spinothalamic system.
These subjects have been extensively reviewed.15–19
Peripheral sensitization reflects plastic changes in
expression of function of a wide variety of cation
channels in nociceptors, including TRPV1 and several
types of voltage-gated sodium (Nav) channels, in
response to axon injury or tissue inflammation. These
mechanisms are not discussed here.
6 Neurology 86 March 15, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Long-term potentiation of excitatory synapses on
spinothalamic neurons. In normal conditions, burst
of activity of nociceptors triggers an activity-dependent
long-term potentiation of the excitatory glutamatergic
synapses onto their target dorsal horn projection
neurons; this is referred to as homosynaptic long-term
potentiation.15,16 Repeated nociceptor activation
also triggers heterosynaptic long-term potentiation,
whereby nociceptive-specific conditioning stimuli lead
to long-lasting facilitation of the responses of dorsal
horn neurons to non-nociceptive Ab- or C-type
afferent inputs. Heterosynaptic long-term potentiation
also allows the spread of the change in synaptic strength
to neighboring nonactivated synapses; this results in
expansion of the stimulus-sensitive territory outside
that of the damaged nerve or beyond the area of tissue
injury.
Long-term potentiation may occur at the presyn-
aptic or postsynaptic levels and largely reflects calcium
(Ca21)–mediated mechanisms.15,16 Postsynaptic long-
term potentiation is triggered by Ca21 influx via
voltage-gated Cav1.2 (L-type) channels and NMDA
receptors, as well as Ca21 release from intracellular
stores triggered by either G-protein-coupled recep-
tors, such as metabotropic glutamate receptors, or
receptor tyrosine kinases, such as the tyrosine kinase
B receptor for brain-derived neurotrophic factor
(BDNF). The resulting increase in intracellular Ca21
triggers several downstream cascades, including those
mediated by a variety of protein kinases, such as
extracellular signal-regulated kinase. This results in
upregulation of a-amino-3-hydroxy-5-methyl-isoxa-
zole propionic acid (AMPA) receptor expression in
the postsynaptic membrane, activation of transcription
and local translation of synaptic proteins, and structural
changes in dendritic spines. In normal conditions, central
sensitization is initiated by a conditioned stimulus from
peptidergic nociceptor afferents and reflects the corelease
of glutamate with substance P; these neuropeptides act
via NK1Rs to elicit membrane depolarization, thereby
promoting NMDA receptor activation. Presynaptic
mechanisms lead to increased release of glutamate from
C afferents in the dorsal horn; this may be promoted by
nitric oxide via protein kinase G–mediated phosphoryl-
ation cascades.15
Plastic changes in primary afferents and excitatory
interneurons. Peripheral axotomy leads to sprouting
of Ab afferents into lamina I and outer lamina II.67
After nerve injury, Ab afferents undergo a phenotypic
change including upregulation of expression of sub-
stance P and other neuropeptides15,16; however,
there is no evidence that these fibers release sub-
stance P to activate NK1R in nociceptive lamina I
neurons.1 Repetitive noxious stimulation also trig-
gers extracellular receptor-activated kinase mediated
 phosphorylation and downregulation of Kv4.2
channels in excitatory neurons; this leads to
increased excitability of these cells, thereby
promoting neuropathic pain.68
Loss of inhibition in the dorsal horn. There is extensive
experimental evidence that manifestations of neuro-
pathic pain, such as mechanical allodynia and itch,
reflect impaired inhibition within dorsal horn circuits69
(figure 2). There are several mechanisms contribut-
ing to loss of GABAergic and glycinergic inhibition
in the dorsal horn in the setting of axonal injury
or tissue inflammation. They include excitotoxic
damage of GABAergic neurons, long-term depression
of inhibitory GABAergic transmission, and reduced
efficacy of inhibitory transmission via GABAA or
glycine receptor channels.69,70 For example, some
GABAergic interneurons in the dorsal horn express
TRPV1 receptors; activation of these receptors may
elicit long-term depression of excitatory inputs from
myelinated fibers to these inhibitory neurons.71 Peripheral
axonal injury also triggers presynaptic Ca21-dependent
signaling that results in global downregulation of the
excitatory drive to GABAergic neurons from
nociceptive Ad and C fibers.72
In the setting of axonal injury, there is activation
of microglia in the dorsal horn.73 Spinal cord microg-
lia has a major role in the genesis of persistent pain via
release of several mediators that regulate synaptic plas-
ticity of the excitatory and inhibitory pain circuits.74
For example, proinflammatory cytokines promote
postsynaptic long-term potentiation of excitatory syn-
apses on dorsal horn projection neurons. Microglia
may also contribute to the reduced efficacy of inhib-
itory transmission in the dorsal horn. Microglia-
derived BDNF downregulates the expression of the
potassium chloride exporter in lamina I neurons; this
leads to a depolarization shift in the equilibrium
potential of chloride, thereby reducing the efficacy
of GABAA and glycine receptor–mediated inhibi-
tion.75 However, GABAergic and glycinergic neurons
may retain their inhibitory effect in the setting of

Figure 2 Loss of inhibition in the dorsal horn as a mechanism of mechanical allodynia and neuropathic itch

(A) Loss of inhibitory control by g-aminobutyric acid (GABA)/glycinergic interneurons in the dorsal horn is an important mechanism for the manifestations of
neuropathic pain. Persistent mechanical allodynia reflects loss of inhibitory control on excitatory interneurons involved in the sequential dorsally projecting
polysynaptic excitatory pathway that allows inputs from low-threshold Ab mechanoreceptors terminating in lamina III to activate nociceptive neurons in
lamina I and thereby elicit pain. This pathway involves vesicular glutamate transporter-3 (VGLUT3)–expressing neurons in lamina III, protein kinase Cg–
expressing interneurons in inner lamina II, and vertical cells of outer lamina II projecting to neurokinin 1 receptor (NK1R)–expressing nociceptive projection
neurons in lamina I. (B) Removal of inhibition by interneurons expressing GABA/dynorphin, glycine, or both also result in neuropathic itch. The multisynaptic
dorsal horn itch pathway involves primary C-pruriceptor afferents that release natriuretic polypeptide B (NPPB), which, acting via natriuretic peptide
receptors, activates a group of interneurons expressing gastric-releasing peptide. These neurons activate a third population of excitatory neurons that
express the gastrin-releasing peptide receptor and, either directly or indirectly, convey the itch sensation via lamina I spinothalamic neurons.

Neurology 86 March 15, 2016 7

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 neuropathy. For example, administration of drugs
that activate GABAA receptors,76 transplantation of
GABA precursor neuron in the dorsal horn,77 or
selective activation of glycinergic neurons62 may
reduce neuropathic pain.
Consequences of impaired inhibition in the dorsal horn.
Mechanical allodynia. Recent studies show that persis-
tent mechanical allodynia involves loss of inhibition
of the excitatory interneurons involved in the sequential
dorsally projecting polysynaptic excitatory pathway that
allows inputs from low-threshold Ab mechanoreceptors
terminating in lamina III to activate nociceptive neurons
in lamina I and thereby elicit pain (figure 2).78 In normal
conditions, this pathway is inactive due to surrounding
feed-forward inhibition via GABA/glycinergic interneu-
rons.42 Both long-term depression of excitatory synapses
on GABAergic neurons71 or toxin-mediated ablation or
silencing of glycinergic neurons62 result in mechanical
allodynia. Removal of glycine inhibition may also enable
tactile stimuli to activate astrocytes; activated astrocytes
may release D-serine, which binds to the glycine-
costimulatory site of the NMDA receptor and thereby
promotes NMDA receptor–mediated allodynia.79
Neuropathic itch. Removal of GABAergic or glycinergic
inhibition also results in neuropathic itch (figure 2). The
multisynaptic dorsal horn itch pathway25 is under tonic
inhibition by specific inhibitory GABA interneurons that
express galanin and the kappa opioid receptor agonist
dynorphin.60,61 These inhibitory interneurons receive in-
puts from C-fiber afferents expressing TRPV1, TRPA1,
and TRMP8 channels; this explains why painful stimuli
or cold relieve itch.60,61 Selective depletion of these inter-
neurons resulted in spontaneous itch and increased sen-
sitivity to pruritic agents, without affecting the responses
to noxious stimuli.60,61 Depletion of glycinergic interneu-
rons also resulted in behavioral manifestations of itch.
PERSPECTIVE Studies incorporating immunohisto-
chemical, electrophysiologic, and genetic approaches
have provided insight into the complex circuits for
transmission and gating of sensory information in the
dorsal horn. These studies have further elucidated the
mechanisms of both the gate control of pain transmis-
sion and the manifestations of neuropathic pain and
itch and provide rationale for new therapeutic ap-
proaches to these symptoms. Among currently available
drugs, gabapentin and pregabalin interact with the a2d
subunit of presynaptic Ca21 channels, reducing their
membrane expression and thereby neurotransmitter
release; opioids act via m-type receptors both presynap-
tically, inhibiting Ca21-triggered release, and postsyn-
aptically, by increasing K1 conductance and thereby
reducing spinothalamic cell excitability; and norepi-
nephrine/serotonin reuptake inhibitors, such as ami-
triptyline or duloxetine, increase the availability of
8 Neurology 86 March 15, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
these monoamines in the dorsal horn. On the basis
of experimental studies in animals with selective dele-
tion GABA/dynorphin neurons,61 the kappa opioid
receptor agonist nalfurafine is approved in Japan for
treatment of itch associated with chronic kidney dis-
ease.80 A recently described dorsal horn circuit for
mechanically induced itch and tonically inhibited by
neuropeptide Y interneurons81 may provide further
therapeutic targets. The major role of glycine in inhib-
itory dorsal horn circuits also provides the rationale for
development of drugs targeting glycinergic transmission
for management of neuropathic pain and itch.
STUDY FUNDING
No targeted funding reported.
DISCLOSURE
E. Benarroch receives a stipend in his capacity as section editor of Clinical
Implications of Neuroscience Research for Neurology. Go to Neurology.
org for full disclosures.
REFERENCES
1. Todd AJ. Neuronal circuitry for pain processing in the
dorsal horn. Nat Rev Neurosci 2010;11:823–836.
2. Braz J, Solorzano C, Wang X, Basbaum AI. Transmitting pain
and itch messages: a contemporary view of the spinal cord
circuits that generate gate control. Neuron 2014;82:522–536.
3. Mendell LM. Constructing and deconstructing the gate
theory of pain. Pain 2014;155:210–216.
4. Ross SE, Hachisuka J, Todd AJ. Spinal microcircuits and
the regulation of itch. In: Carstens E, Akiyama T, eds.
Itch: Mechanisms and Treatment. Boca Raton, FL:
CRC Press/Taylor & Francis; 2014.
5. Bautista DM, Wilson SR, Hoon MA. Why we scratch an
itch: the molecules, cells and circuits of itch. Nat Neurosci
2014;17:175–182.
6. Prescott SA, Ratte S. Pain processing by spinal microcir-
cuits: afferent combinatorics. Curr Opin Neurobiol 2012;
22:631–639.
7. Davidson S, Giesler GJ. The multiple pathways for itch
and their interactions with pain. Trends Neurosci 2010;
33:550–558.
8. Han L, Dong X. Itch mechanisms and circuits. Annu Rev
Biophys 2014;43:331–355.
9. LaMotte RH, Dong X, Ringkamp M. Sensory neurons and
circuits mediating itch. Nat Rev Neurosci 2014;15:19–31.
10. Hoon MA. Molecular dissection of itch. Curr Opin Neu-
robiol 2015;34:61–66.
11. Campbell JN, Meyer RA. Mechanisms of neuropathic
pain. Neuron 2006;52:77–92.
12. Baron R, Binder A, Wasner G. Neuropathic pain: diagno-
sis, pathophysiological mechanisms, and treatment. Lancet
Neurol 2010;9:807–819.
13. Denk F, McMahon SB. Chronic pain: emerging evidence for
the involvement of epigenetics. Neuron 2012;73:435–444.
14. Truini A, Garcia-Larrea L, Cruccu G. Reappraising neu-
ropathic pain in humans: how symptoms help disclose
mechanisms. Nat Rev Neurol 2013;9:572–582.
15. Luo C, Kuner T, Kuner R. Synaptic plasticity in patho-
logical pain. Trends Neurosci 2014;37:343–355.
16. von Hehn CA, Baron R, Woolf CJ. Deconstructing the
neuropathic pain phenotype to reveal neural mechanisms.
Neuron 2012;73:638–652.
 17. Prescott SA, Ma Q, De Koninck Y. Normal and abnormal
coding of somatosensory stimuli causing pain. Nat Neuro-
sci 2014;17:183–191.
18. Dhand A, Aminoff MJ. The neurology of itch. Brain
2014;137:313–322.
19. Misery L, Brenaut E, Le Garrec R, et al. Neuropathic
pruritus. Nat Rev Neurol 2014;10:408–416.
20. Rexed B. The cytoarchitectonic organization of the spinal
cord in the cat. J Comp Neurol 1952;96:414–495.
21. Liu Q, Dong X. The role of the Mrgpr receptor family in
itch. Handb Exp Pharmacol 2015;226:71–88.
22. Akiyama T, Carstens E. Neural processing of itch. Neu-
roscience 2013;250:697–714.
23. Wilson SR, Gerhold KA, Bifolck-Fisher A, et al. TRPA1 is
required for histamine-independent, Mas-related G protein-
coupled receptor-mediated itch. Nat Neurosci 2011;14:
595–602.
24. Schmelz M, Schmidt R, Weidner C, Hilliges M,
Torebjork HE, Handwerker HO. Chemical response pat-
tern of different classes of C-nociceptors to pruritogens
and algogens. J Neurophysiol 2003;89:2441–2448.
25. Mishra SK, Hoon MA. The cells and circuitry for itch
responses in mice. Science 2013;340:968–971.
26. Han L, Ma C, Liu Q, et al. A subpopulation of nocicep-
tors specifically linked to itch. Nat Neurosci 2013;16:
174–182.
27. McGlone F, Wessberg J, Olausson H. Discriminative and affec-
tive touch: sensing and feeling. Neuron 2014;82:737–755.
28. Bardoni R, Tawfik VL, Wang D, et al. Delta opioid re-
ceptors presynaptically regulate cutaneous mechanosensory
neuron input to the spinal cord dorsal horn. Neuron 2014;
81:1312–1327.
29. Dhaka A, Earley TJ, Watson J, Patapoutian A. Visualizing
cold spots: TRPM8-expressing sensory neurons and their
projections. J Neurosci 2008;28:566–575.
30. Vriens J, Nilius B, Voets T. Peripheral thermosensation in
mammals. Nat Rev Neurosci 2014;15:573–589.
31. Han ZS, Zhang ET, Craig AD. Nociceptive and thermor-
eceptive lamina I neurons are anatomically distinct. Nat
Neurosci 1998;1:218–225.
32. Almarestani L, Waters SM, Krause JE, Bennett GJ, Ribeiro-
da-Silva A. Morphological characterization of spinal cord dor-
sal horn lamina I neurons projecting to the parabrachial
nucleus in the rat. J Comp Neurol 2007;504:287–297.
33. Willis WD Jr. The somatosensory system, with emphasis
on structures important for pain. Brain Res Rev 2007;55:
297–313.
34. Craig AD. Topographically organized projection to poste-
rior insular cortex from the posterior portion of the ventral
medial nucleus in the long-tailed macaque monkey.
J Comp Neurol 2014;522:36–63.
35. De Felipe C, Herrero JF, O’Brien JA, et al. Altered noci-
ception, analgesia and aggression in mice lacking the recep-
tor for substance P. Nature 1998;392:394–397.
36. Borsook D, Upadhyay J, Klimas M, et al. Decision-mak-
ing using fMRI in clinical drug development: revisiting
NK-1 receptor antagonists for pain. Drug Discov Today
2012;17:964–973.
37. Almarestani L, Waters SM, Krause JE, Bennett GJ, Ri-
beiro-da-Silva A. De novo expression of the neurokinin
1 receptor in spinal lamina I pyramidal neurons in poly-
arthritis. J Comp Neurol 2009;514:284–295.
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
38. Braz JM, Nassar MA, Wood JN, Basbaum AI. Parallel
“pain” pathways arise from subpopulations of primary
afferent nociceptor. Neuron 2005;47:787–793.
39. Hantman AW, van den Pol AN, Perl ER. Morphological
and physiological features of a set of spinal substantia
gelatinosa neurons defined by green fluorescent protein
expression. J Neurosci 2004;24:836–842.
40. Yasaka T, Tiong SY, Hughes DI, Riddell JS, Todd AJ.
Populations of inhibitory and excitatory interneurons in
lamina II of the adult rat spinal dorsal horn revealed by a
combined electrophysiological and anatomical approach.
Pain 2010;151:475–488.
41. Polgar E, Durrieux C, Hughes DI, Todd AJ. A quantita-
tive study of inhibitory interneurons in laminae I-III of the
mouse spinal dorsal horn. PLoS One 2013;8:e78309.
42. Duan B, Cheng L, Bourane S, et al. Identification of spinal
circuits transmitting and gating mechanical pain. Cell
2014;159:1417–1432.
43. Punnakkal P, von Schoultz C, Haenraets K, Wildner H,
Zeilhofer HU. Morphological, biophysical and synaptic
properties of glutamatergic neurons of the mouse spinal
dorsal horn. J Physiol 2014;592:759–776.
44. Smith KM, Boyle KA, Madden JF, et al. Functional het-
erogeneity of calretinin-expressing neurons in the mouse
superficial dorsal horn: implications for spinal pain pro-
cessing. J Physiol 2015;593:4319–4339.
45. Hughes DI, Sikander S, Kinnon CM, et al. Morphological,
neurochemical and electrophysiological features of parvalbumin-
expressing cells: a likely source of axo-axonic inputs in the
mouse spinal dorsal horn. J Physiol 2012;590:3927–3951.
46. Xu Y, Lopes C, Wende H, et al. Ontogeny of excitatory
spinal neurons processing distinct somatic sensory modal-
ities. J Neurosci 2013;33:14738–14748.
47. Peirs C, Patil S, Bouali-Benazzouz R, Artola A, Landry M,
Dallel R. Protein kinase C gamma interneurons in the rat
medullary dorsal horn: distribution and synaptic inputs to
these neurons, and subcellular localization of the enzyme.
J Comp Neurol 2014;522:393–413.
48. Knowlton WM, Palkar R, Lippoldt EK, et al. A sensory-
labeled line for cold: TRPM8-expressing sensory neurons
define the cellular basis for cold, cold pain, and cooling-
mediated analgesia. J Neurosci 2013;33:2837–2848.
49. Zhang J, Cavanaugh DJ, Nemenov MI, Basbaum AI. The
modality-specific contribution of peptidergic and non-
peptidergic nociceptors is manifest at the level of dorsal horn
nociresponsive neurons. J Physiol 2013;591:1097–1110.
50. Zheng J, Lu Y, Perl ER. Inhibitory neurones of the spinal
substantia gelatinosa mediate interaction of signals from
primary afferents. J Physiol 2010;588:2065–2075.
51. Uta D, Furue H, Pickering AE, et al. TRPA1-expressing
primary afferents synapse with a morphologically identi-
fied subclass of substantia gelatinosa neurons in the adult
rat spinal cord. Eur J Neurosci 2010;31:1960–1973.
52. Wang H, Zylka MJ. Mrgprd-expressing polymodal noci-
ceptive neurons innervate most known classes of substantia
gelatinosa neurons. J Neurosci 2009;29:13202–13209.
53. Scherrer G, Imamachi N, Cao YQ, et al. Dissociation of
the opioid receptor mechanisms that control mechanical
and heat pain. Cell 2009;137:1148–1159.
54. Lu Y, Perl ER. Modular organization of excitatory circuits
between neurons of the spinal superficial dorsal horn (lam-
inae I and II). J Neurosci 2005;25:3900–3907.
55. Wang X, Zhang J, Eberhart D, et al. Excitatory superficial
dorsal horn interneurons are functionally heterogeneous
Neurology 86 March 15, 2016 9
 and required for the full behavioral expression of pain and
itch. Neuron 2013;78:312–324.
56. Miraucourt LS, Dallel R, Voisin DL. Glycine inhibitory
dysfunction turns touch into pain through PKCgamma
interneurons. PLoS One 2007;2:e1116.
57. Sewards TV, Sewards M. Separate, parallel sensory and
hedonic pathways in the mammalian somatosensory sys-
tem. Brain Res Bull 2002;58:243–260.
58. Melzack R, Wall PD. Pain mechanisms: a new theory.
Science 1965;150:971–979.
59. Yasaka T, Kato G, Furue H, et al. Cell-type-specific excit-
atory and inhibitory circuits involving primary afferents in
the substantia gelatinosa of the rat spinal dorsal horn
in vitro. J Physiol 2007;581:603–618.
60. Ross SE, Mardinly AR, McCord AE, et al. Loss of inhib-
itory interneurons in the dorsal spinal cord and elevated
itch in Bhlhb5 mutant mice. Neuron 2010;65:886–898.
61. Kardon AP, Polgar E, Hachisuka J, et al. Dynorphin acts
as a neuromodulator to inhibit itch in the dorsal horn of
the spinal cord. Neuron 2014;82:573–586.
62. Foster E, Wildner H, Tudeau L, et al. Targeted ablation,
silencing, and activation establish glycinergic dorsal horn
neurons as key components of a spinal gate for pain and
itch. Neuron 2015;85:1289–1304.
63. Lu Y, Perl ER. Selective action of noradrenaline and sero-
tonin on neurones of the spinal superficial dorsal horn in
the rat. J Physiol 2007;582:127–136.
64. Sikand P, Shimada SG, Green BG, LaMotte RH. Similar
itch and nociceptive sensations evoked by punctate cuta-
neous application of capsaicin, histamine and cowhage.
Pain 2009;144:66–75.
65. Sandroni P, Martin DP, Bruce BK, Rome JD. Congenital
idiopathic inability to perceive pain: a new syndrome of
insensitivity to pain and itch with preserved small fibers.
Pain 2006;122:210–215.
66. Indo Y. Nerve growth factor, pain, itch and inflammation:
lessons from congenital insensitivity to pain with anhidro-
sis. Expert Rev Neurother 2010;10:1707–1724.
67. Woolf CJ, Shortland P, Coggeshall RE. Peripheral nerve
injury triggers central sprouting of myelinated afferents.
Nature 1992;355:75–78.
68. Huang HY, Cheng JK, Shih YH, Chen PH, Wang CL,
Tsaur ML. Expression of A-type K channel alpha subunits
10 Neurology 86 March 15, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Kv 4.2 and Kv 4.3 in rat spinal lamina II excitatory inter-
neurons and colocalization with pain-modulating mole-
cules. Eur J Neurosci 2005;22:1149–1157.
69. Zeilhofer HU, Wildner H, Yevenes GE. Fast synaptic
inhibition in spinal sensory processing and pain control.
Physiol Rev 2012;92:193–235.
70. Braz JM, Wang X, Guan Z, Rubenstein JL, Basbaum AI.
Transplant-mediated enhancement of spinal cord GA-
BAergic inhibition reverses paclitaxel-induced mechanical
and heat hypersensitivity. Pain 2015;156:1084–1091.
71. Kim YH, Back SK, Davies AJ, et al. TRPV1 in GABAergic
interneurons mediates neuropathic mechanical allodynia
and disinhibition of the nociceptive circuitry in the spinal
cord. Neuron 2012;74:640–647.
72. Leitner J, Westerholz S, Heinke B, et al. Impaired excit-
atory drive to spinal GABAergic neurons of neuropathic
mice. PLoS One 2013;8:e73370.
73. Graeber MB, Christie MJ. Multiple mechanisms of
microglia: a gatekeeper’s contribution to pain states. Exp
Neurol 2012;234:255–261.
74. Taves S, Berta T, Chen G, Ji RR. Microglia and spinal
cord synaptic plasticity in persistent pain. Neural Plast
2013;2013:753656.
75. Coull JA, Beggs S, Boudreau D, et al. BDNF from microglia
causes the shift in neuronal anion gradient underlying neu-
ropathic pain. Nature 2005;438:1017–1021.
76. Knabl J, Witschi R, Hosl K, et al. Reversal of pathological
pain through specific spinal GABAA receptor subtypes.
Nature 2008;451:330–334.
77. Braz JM, Sharif-Naeini R, Vogt D, et al. Forebrain GABAergic
neuron precursors integrate into adult spinal cord and reduce
injury-induced neuropathic pain. Neuron 2012;74:663–675.
78. Peirs C, Williams SP, Zhao X, et al. Dorsal horn circuits
for persistent mechanical pain. Neuron 2015;87:797–812.
79. Miraucourt LS, Peirs C, Dallel R, Voisin DL. Glycine
inhibitory dysfunction turns touch into pain through
astrocyte-derived D-serine. Pain 2011;152:1340–1348.
80. Kumagai H, Ebata T, Takamori K, et al. Efficacy and
safety of a novel k-agonist for managing intractable pruri-
tus in dialysis patients. Am J Nephrol 2012;36:175–183.
81. Bourane S, Duan B, Koch SC, et al. Gate control of
mechanical itch by a subpopulation of spinal cord inter-
neurons. Science 2015;350:550–554.
 Dorsal horn circuitry: Complexity and implications for mechanisms of neuropathic
pain
Eduardo E. Benarroch
Neurology published online February 17, 2016
DOI 10.1212/WNL.0000000000002478

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